I risultati del nostro studio mostrano che pazienti con diversi disturbi psicotici, presentano alterazioni del SERT, dimostrate sia dal ridotto binding della 3H-PAR, che dalla diminuzione dell’uptake della 3H-5-HT in entrambi i modelli che abbiamo preso in considerazione, ovvero sia nelle piastrine che nei linfociti..
Il numero di Hill vicino all’unità conferma l’esistenza di un solo sito di legame corrispondente proprio alla proteina trasportatrice della 5-HT, che risulta identica nelle piastrine e nei neuroni presinaptici serotoninergici, come dimostrato dagli studi di clonaggio e sequenziazione delle due strutture (Lesch e coll. 1990).
Nel nostro studio abbiamo quindi rilevato una riduzione significativa del binding della 3H-PAR e della velocità dell’uptake della 5-HT in pazienti psicotici rispetto ai sani. Questo significa che si tratta di una diminuzione reale delle proteine che trasportano la 5-HT, e che queste proteine trasportano la 5-HT con un’efficienza minore.
La nostra ricerca rappresenta il primo studio che ha evidenziato un decremento del SERT in alcuni disturbi psicotici, attraverso il binding della 3H-PAR sia nelle piastrine che nei linfociti.
Precedentemente, infatti, erano stati riportati decrementi del SERT piastrinico marcato però con la 3H-IMI, che è un ligando meno selettivo (Marazziti e coll. 1987).
Occorre anche ricordare che altri studi riportano sia un incremento del SERT (Desmet e coll, 1987), sia nessuna differenza tra il gruppo di pazienti e quello dei soggetti sani di controllo (Gentsch e coll, 1985;Weizman e coll, 1987).
Per quanto riguarda la terapia farmacologica dei pazienti da noi esaminati, è importante sottolineare che i farmaci assunti al momento del dosaggio, ovvero stabilizzanti dell’umore, benzodiazepine e antipsicotici, sono composti che sembrano non interferire con la 3H-PAR, almeno in vitro (Rotondo e coll, 1989). Possiamo quindi formulare l’ipotesi che un’alterazione nella densità delle proteine trasportatrici della 5-HT (riscontrata a livello delle cellule ematiche periferiche) potrebbe, qualora si manifestasse anche a livello centrale, avere importanti effetti sulla disponibilità intrasinaptica della 5-HT, il che sarebbe alla base dei sintomi osservati in diversi disturbi psichiatrici. Tuttavia, al momento, non possiamo escludere la possibilità che la diminuzione della densità del SERT possa rappresentare un elemento compensatorio piuttosto che un fenomeno primario. E' comunque difficile
comprendere il significato della riduzione del SERT nelle psicosi, considerando che altri studi hanno riscontrato analoghe alterazioni di questa struttura in altre patologie psichiatriche come la depressione, il disturbo da attacci di panico, il DOC, i disturbi del comportamento alimentare, i tentativi di suicidio; siamo quindi di fronte ad un marker che non è sicuramente specifico per un certo disturbo.
Ugualmente non è chiaro se la riduzione del trasportatore sia la causa o la conseguenza dell' alterazione della quantità intra- sinaptica di 5-HT.
In generale, si ritiene che esso rappresenti un marker aspecifico che testimonia il coinvolgimento dei neuroni presinaptici serotoninergici, e che sia transnosografico, ossia non legato ad una patologia specifica, ma ad aspetti dimensionali che potrebbero essere comuni a diverse condizioni fisiopatologiche.
Possiamo, però, sottolineare che un numero crescente di dati recenti ha evidenziato che il ruolo del SERT potrebbe non essere limitato alla rimozione del neurotrasmettitore dal vallo sinaptico, ma che questa struttura possa svolgere una funzione fondamentale nello sviluppo cerebrale e nei fenomeni di plasticità e neurodegenerazione.
Per esempio, è stato dimostrato che, mentre nell’adulto l’espressione del trasportatore è limitata ai nuclei del rafe, nel neonato è presente anche nella corteccia del cingolo e nel talamo, con una innervazione transitoria della corteccia somatosensoriale, visiva, uditiva e ventrobasale del talamo (Bruening e coll, 1997). E’ stata così formulata l’ipotesi che un’alterazione del normale processo di espressione del trasportatore della 5-HT, così come una persistenza prolungata nella vita post-natale, potrebbe alterare lo sviluppo normale del cervello, il che rappresenterebbe la base di vulnerabilità per alcuni disturbi, probabilmente sottesi da questi processi, come l’autismo e la schizofrenia.
Per quanto riguarda gli studi sull’ uptake della 5-HT effettuati sui pazienti è stata evidenziata una significativa diminuzione della velocità massima (Vmax), ciò conferma una riduzione della funzionalità del SERT nelle psicosi. Questo dato riflette la riduzione precedentemente evidenziata con il binding della 3H-PAR, ma potrebbe essere dovuto anche a fenomeni di fosforilazione del SERT da parte di proteine chinasi, in particolare della proteina chinasi C (PKC), la cui attività potrebbe essere aumentata nei pazienti affetti da disturbi psicotici, o dalla proteina chinasi A (PKA), la cui attività potrebbe, invece, essere ridotta.
Per quanto riguarda i linfociti, ulteriori studi potrebbero permetterci di valutare l’espressione del SERT mediante tecniche di biologia molecolare, studi non effettuabili sulle piastrine in quanto prive di nucleo. Infatti, la presenza del trasportatore della 5-HT in cellule nucleate quali i linfociti, potrebbe facilitare lo studio, anche da un punto di vista genetico, di questa struttura e la regolazione dei suoi processi trascrizionali in periferia, sebbene vi sia la possibilità che il trasportatore della 5-HT possa essere regolato diversamente in cellule nucleate e in cellule non-nucleate così come nel sangue rispetto al SNC.
Studi futuri con tecniche di ibridazione in-situ potrebbero consentire di determinare se una riduzione del legame della 3H- paroxetina sia dovuto o meno ad una alterata espressione della proteina di trasporto.
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